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Research Article Open access CC BY 4.0

Impact of TP53 Gain-of-Function Mutations on Metabolic Reprogramming in Prostate Cancer Progression

Farida Jazuli Usman, Dikshat Gopal Gupta, Sarki A Abdulkadir, Ibrahim Muhammad Usman, Adamu Jibrin Alhassan, Young A Yoo, Haris Jaafar Bello, Binta G. Kurfi, Kamaluddeen Babagana

Asian Journal of Biochemistry, Genetics and Molecular Biology · pp. 17–31 · Published 10 Jan 2025

10.9734/ajbgmb/2025/v17i1434

Abstract

Despite advancements in the treatment of advanced prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC), the disease remains lethal, often developing resistance to conventional therapies such as androgen deprivation therapy (ADT) and chemotherapy. Therapy resistance poses a significant challenge, particularly in aggressive forms of prostate cancer. Data on TP53 mutations, especially gain-of-function (GOF) mutations, and their specific impact on prostate cancer metabolism remain limited, underscoring the need for a deeper understanding to uncover new therapeutic avenues. This study aimed to explore the metabolic consequences of TP53 GOF mutations (R175H and R273H) in prostate cancer progression using metabolomics analysis. Approximately 300 metabolites were significantly altered across PC3-GFP (KO), PC3-TP53WT (WT), and PC3-TP53 mutant (R175H & R273H) models. Key findings revealed dysregulation of essential metabolites, such as α-ketoglutarate and spermidine, which support cancer cell survival and progression. These insights not only enhance our understanding of the interplay between TP53 mutations and metabolic alterations but also identify potential biomarkers for prognosis and therapeutic targeting in therapy-resistant prostate cancer. In the TP53-R175H mutant, numerous essential metabolites were dysregulated (downregulated: glutamine, GAP/DHAP, and α-ketoglutarate; Upregulated: deoxyuridine, spermidine, and pseudouridine) when compared with the control (KO) thereby causing metabolic shifts that favor cancer cell survival. Conversely, metabolites such as GlaNAC/GlcNAC, adenosine, acetoacetic acid, acetylcholine, octopamine, itaconic acid, lactic acid, and NADP+ are all downregulated in the R273H mutant. While spermine, spermidine, N-acetyl-DL-serine, pseudouridine, deoxyguanosine, sucrose, and AMP/dGMP are upregulated by the R273H mutant but downregulated in GFP (KO). These findings showed that TP53 GOF mutations (R175H & R273H) cause metabolic alterations in numerous metabolites essential for tumor survival and progression. Furthermore, it may provide therapeutic benefits by identifying appropriate biomarkers that could be used as diagnostic and/or prognostic tools for prostate cancer.

Prostate cancer PC-3 TP53Wild-Type TP53-R175H TP53-R273H metabolomics

References (34)

  1. 1 Oxidative Stress in Cancer [DOI]
  2. 2 Mutant p53 as a guardian of the cancer cell [DOI]
  3. 3 Treatment of Advanced Prostate Cancer [DOI]
  4. 4 NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications [DOI]
  5. 5 Tumour-associated mutant p53 drives the Warburg effect [DOI]
  6. 6 α-Ketoglutarate links p53 to cell fate during tumour suppression [DOI]
  7. 7 Mutant p53 in cancer therapy—the barrier or the path [DOI]
  8. 8 Metabolic reprogramming in prostate cancer [DOI]
  9. 9 SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells [DOI]
  10. 10 TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer [DOI]
  11. 11 Tp53-induced Glycolysis and Apoptosis Regulator (TIGAR) Protects Glioma Cells from Starvation-induced Cell Death by Up-regulating Respiration and Improving Cellular Redox Homeostasis [DOI]
  12. 12 Metastatic prostate cancer remains incurable, why? [DOI]
  13. 13 Cancer metabolism and carcinogenesis [DOI]
  14. 14 Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells [DOI]
  15. 15 How mutations shape p53 interactions with the genome to promote tumorigenesis and drug resistance [DOI]
  16. 16 EXPRESSION OF CONCERN: Functional p53 determines docetaxel sensitivity in prostate cancer cells [DOI]
  17. 17 Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high ROS levels [DOI]
  18. 18 The crisscross between p53 and metabolism in cancer [DOI]
  19. 19 Metabolic remodeling in cancer and senescence and its therapeutic implications [DOI]
  20. 20 ‘Evaluation of adverse prognostic gene alterations & MRD positivity in BCR::ABL1-like B-lineage acute lymphoblastic leukaemia patients, in a resource-constrained setting [DOI]
  21. 21 Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction [DOI]
  22. 22 TP53 mutation hits energy metabolism and increases glycolysis in breast cancer [DOI]
  23. 23 Molecular mechanisms of A3 adenosine receptor-induced G1 cell cycle arrest and apoptosis in androgen-dependent and independent prostate cancer cell lines: involvement of intrinsic pathway [DOI]
  24. 24 Prostate cancer-specific hallmarks of amino acids metabolism: Towards a paradigm of precision medicine [DOI]
  25. 25 Revisiting the Role of p53 in Prostate Cancer [DOI]
  26. 26 Genomic and proteomic characterization of Philadelphia‐like B‐lineage acute lymphoblastic leukemia: A report of Indian patients [DOI]
  27. 27 Hematological, clinical, immunophenotypic characterization, and treatment outcomes of prognostically significant genetic subtypes of B‐lineage acute lymphoblastic leukemia: A report of 1021 patients from India [DOI]
  28. 28 Spermidine/Spermine N1 -Acetyltransferase-1 as a Diagnostic Biomarker in Human Cancer [DOI]
  29. 29 Metabolic utilization of exogenous pyruvate by mutant p53 (R175H) human melanoma cells promotes survival under glucose depletion [DOI]
  30. 30 974 FUNCTIONAL P53 DETERMINES DOCETAXEL SENSITIVITY IN PROSTATE CANCER CELLS [DOI]
  31. 31 TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use [DOI]
  32. 32 The developing mind: how relationships and the brain interact to shape who we are [DOI]
  33. 33 TP53 Inhibited AR Signaling Promote Enzalutamide Resistance in LNCaP cell [DOI]
  34. 34 Abstract 1712: Targeting asparagine dependency as a therapy for TP53-mutated castration-resistant prostate cancer [DOI]

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